Dipeptidyl peptidase inhibitors for the treatment of diabetes

ABSTRACT

Compounds having Formula I, including pharmaceutically acceptable salts and prodrugs thereof: (I) are inhibitors of the dipeptidyl peptidase-IV enzyme (DP-IV), and are useful in the treatment of DP-IV mediated diseases and conditions, such as non-insulin dependent diabetes mellitus

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No.PCT/US02/19441, filed Jun. 19, 2002, which claims the benefit under 35U.S.C. 119(e) of U.S. Provisional Application No. 60/299,505, filed Jun.20, 2001.

FIELD OF THE INVENTION

The instant invention is concerned with a novel class of dipeptidylpeptidase inhibitors, including pharmaceutically acceptable salts andprodrugs thereof, which are useful as therapeutic compounds,particularly in the treatment of Type 2 diabetes mellitus, oftenreferred to as non-insulin dependent diabetes (NIDDM), and of conditionsthat are often associated with this disease, such as obesity and lipiddisorders.

BACKGROUND OF THE INVENTION

Diabetes refers to a disease process derived from multiple causativefactors and characterized by elevated levels of plasma glucose orhyperglycemia in the fasting state or after administration of glucoseduring an oral glucose tolerance test. Persistent or uncontrolledhyperglycemia is associated with increased and premature morbidity andmortality. Often abnormal glucose homeostasis is associated bothdirectly and indirectly with alterations of the lipid, lipoprotein andapolipoprotein metabolism and other metabolic and hemodynamic disease.Therefore patients with Type 2 diabetes mellitus are at especiallyincreased risk of macrovascular and microvascular complications,including coronary heart disease, stroke, peripheral vascular disease,hypertension, nephropathy, neuropathy, and retinopathy. Therefore,therapeutical control of glucose homeostasis, lipid metabolism andhypertension are critically important in the clinical management andtreatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), patientsproduce little or no insulin, the hormone which regulates glucoseutilization. In type 2 diabetes, or noninsulin dependent diabetesmellitus (NIDDM), patients often have plasma insulin levels that are thesame or even elevated compared to nondiabetic subjects; however, thesepatients have developed a resistance to the insulin stimulating effecton glucose and lipid metabolism in the main insulin-sensitive tissues,which are muscle, liver and adipose tissues, and the plasma insulinlevels, while elevated, are insufficient to overcome the pronouncedinsulin resistance.

Insulin resistance is not primarily due to a diminished number ofinsulin receptors but to a post-insulin receptor binding defect that isnot yet understood. This resistance to insulin responsiveness results ininsufficient insulin activation of glucose uptake, oxidation and storagein muscle and inadequate insulin repression of lipolysis in adiposetissue and of glucose production and secretion in the liver.

The available treatments for type 2 diabetes, which have not changedsubstantially in many years, have recognized limitations. While physicalexercise and reductions in dietary intake of calories will dramaticallyimprove the diabetic condition, compliance with this treatment is verypoor because of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of saturatedfat. Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, whichstimulate the pancreatic β-cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinide becomeineffective, can result in insulin concentrations high enough tostimulate the very insulin-resistant tissues. However, dangerously lowlevels of plasma glucose can result from administration of insulin orinsulin secretagogues (sulfonylureas or meglitinide), and an increasedlevel of insulin resistance due to the even higher plasma insulin levelscan occur. The biguanides increase insulin sensitivity resulting in somecorrection of hyperglycemia. However, the two biguanides, phenformin andmetformin, can induce lactic acidosis and nausea/diarrhea. Metformin hasfewer side effects than phenformin and is often prescribed for thetreatment of Type 2 diabetes.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a morerecently described class of compounds with potential for amelioratingmany symptoms of type 2 diabetes. These agents substantially increaseinsulin sensitivity in muscle, liver and adipose tissue in severalanimal models of type 2 diabetes resulting in partial or completecorrection of the elevated plasma levels of glucose without occurrenceof hypoglycemia. The glitazones that are currently marketed are agonistsof the peroxisome proliferator activated receptor (PPAR), primarily thePPAR-gamma subtype. PPAR-gamma agonism is generally believed to beresponsible for the improved insulin sensititization that is observedwith the glitazones. Newer PPAR agonists that are being tested fortreatment of Type II diabetes are agonists of the alpha, gamma or deltasubtype, or a combination of these, and in many cases are chemicallydifferent from the glitazones (i.e., they are not thiazolidinediones).Serious side effects (e.g. liver toxicity) have occurred with some ofthe glitazones, such as troglitazone.

Additional methods of treating the disease are still underinvestigation. New biochemical approaches that have been recentlyintroduced or are still under development include treatment withalpha-glucosidase inhibitors (e.g. acarbose) and protein tyrosinephosphatase-1B (PTP-1B) inhibitors.

Compounds that are inhibitors of the dipeptidyl peptidase-IV enzyme arealso under investigation as drugs that may be useful in the treatment ofdiabetes, and particularly type 2 diabetes. See for example WO 97/40832and WO 98/19998. The usefulness of DP-IV inhibitors in the treatment oftype 2 diabetes is based on the fact that DP-IV in vivo readilyinactivates glucagon like peptide-1 (GLP-1) and gastric inhibitorypeptide (GIP). GLP-1 and GIP are incretins and are produced when food isconsumed. The incretins stimulate production of insulin. Inhibition ofDP-IV leads to decreased inactivation of the incretins, and this in turnresults in increased effectiveness of the incretins in stimulatingproduction of insulin by the pancreas. DP-IV inhibition thereforeresults in an increased level of serum insulin. Advantageously, sincethe incretins are produced by the body only when food is consumed, DP-IVinhibition is not expected to increase the level of insulin atinappropriate times, such as between meals, which can lead toexcessively low blood sugar (hypoglycemia). Inhibition of DP-IV istherefore expected to increase insulin without increasing the risk ofhypoglycemia, which is a dangerous side effect associated with the useof insulin secretagogues.

DP-IV inhibitors may also have other therapeutic utilities, as discussedelsewhere in this application. DP-IV inhibitors have not been studiedextensively to date, especially for utilities other than diabetes. Newcompounds are needed so that improved DP-IV inhibitors can be found forthe treatment of diabetes and potentially other diseases and conditions.

SUMMARY OF THE INVENTION

A new class of DP-IV inhibitors is described herein. They may beeffective in the treatment of Type 2 diabetes and other DP-IV modulateddiseases. The class of compounds is defined by formula I below,including pharmaceutically acceptable salts and prodrugs.

In the compounds having Formula I:

-   -   X is selected from CH₂, O and NR⁷;    -   Ar is selected from the group consisting of:        -   (1) phenyl,        -   (2) naphthyl,        -   (3) thienyl, and        -   (4) benzothiophenyl,            wherein Ar is optionally substituted with 1–5 groups R¹;    -   R¹ is selected from the group consisting of:        -   (1) halogen,        -   (2) C₁₋₆alkyl, which is linear or branched and is optionally            substituted with 1–5 halogens,        -   (3) OC₁₋₆alkyl, which is linear or branched and is            optionally substituted with 1–5 halogens, and        -   (4) CN;    -   Each R² is independently selected from the group consisting of        H, OH, halogen and C₁₋₆alkyl, wherein C₁₋₆alkyl is linear or        branched and is optionally substituted with 1–5 halogens,        wherein the two groups R² can optionally be joined to form a        C₃₋₆cycloalkyl, which is optionally substituted with 1–3        halogens;    -   Each R³ is independently selected from the group consisting of        H, halogen and C₁₋₆alkyl, wherein C₁₋₆alkyl is linear or        branched and is optionally substituted with 1–5 halogens,        wherein the two groups R³ can optionally be joined to form a        C₃₋₆cycloalkyl, which is optionally substituted with 1–3        halogens;    -   Q is selected from the group consisting of:        -   (1) H,        -   (2) C₁₋₁₀alkyl, which is linear or branched and is            optionally substituted with 1–6 substituents independently            selected from 0–5 halogens and 0–1 substituent selected from            -   (a) phenyl,            -   (b) naphthyl,            -   (c) a 5 or 6-membered heterocycle which may be saturated                or unsaturated comprising 1–4 heteroatoms independently                selected from N, S and O,            -   (d) an 8–10 membered bicyclic ring system which may be                saturated or unsaturated which comprises (a) two fused                heterocyclic rings, each heterocyclic ring having 1–4                heteroatoms independently selected from N, S and O,                or (b) a phenyl ring fused to a 5-or 6-membered                heterocycle having 1–3 heteroatoms selected from N, S                and O,            -   (e) CO₂H,            -   (f) CO₂C₁₋₆alkyl, and            -   (g) CONR⁴R⁴                wherein said phenyl and naphthyl are optionally                substituted with 1–5 substituents independently selected                from C₁₋₆alkyl, OC₁₋₆alkyl, hydroxy and halogen, said                C₁₋₆alkyl and OC₁₋₆alkyl being linear or branched and                optionally substituted with 1–5 halogens, and wherein                said CO₂C₁₋₆alkyl is linear or branched, and wherein                said 5 or 6-membered heterocycle and said 8–10 membered                bicyclic ring system are optionally substituted with 1–5                substituents independently selected from C₁₋₆alkyl,                OC₁₋₆alkyl, oxo, hydroxy and halogen, said C₁₋₆alkyl and                OC₁₋₆alkyl being linear or branched and optionally                substituted with 1–5 halogens, and wherein said                CO₂C₁₋₆alkyl is linear or branched;        -   (3) CN;        -   (4) Phenyl, which is optionally substituted with 1–5            substituents independently selected from C₁₋₆alkyl,            OC₁₋₆alkyl, hydroxy and halogen, said C₁₋₆alkyl and            OC₁₋₆alkyl being linear or branched and optionally            substituted with 1–5 halogens;        -   (5) Naphthyl, which is optionally substituted with 1–5            substituents independently selected from C₁₋₆alkyl,            OC₁₋₆alkyl, hydroxy and halogen, said C₁₋₆alkyl and            OC₁₋₆alkyl being linear or branched and optionally            substituted with 1–5 halogens,        -   (6) a 5 or 6-membered heterocycle which may be saturated or            unsaturated comprising 1–4 heteroatoms independently            selected from N, S and O, said heterocycle being optionally            substituted with 1–5 substituents independently selected            from oxo, hydroxy, C₁₋₆alkyl, OC₁₋₆alkyl and halogen, said            C₁₋₆alkyl and OC₁₋₆alkyl being linear or branched and            optionally substituted with 1–5 halogens, and        -   (7) an 8–10 membered bicyclic ring system which may be            saturated or unsaturated which comprises (a) two fused            heterocyclic rings, each heterocyclic ring having 1–4            heteroatoms independently selected from N, S and O, or (b) a            phenyl ring fused to a 5-or 6-membered heterocycle having            1–3 heteroatoms selected from N, S and O, wherein said            bicyclic ring system is optionally substituted with 1–5            substituents independently selected from oxo, hydroxy,            C₁₋₆alkyl, OC₁₋₆alkyl and halogen, said C₁₋₆alkyl and            OC₁₋₆alkyl being linear or branched and optionally            substituted with 1–5 halogens;    -   R⁴ is selected from        -   (1) H, and        -   (2) R⁵;    -   R⁵ is selected from the group consisting of phenyl,        C₃₋₆cycloalkyl and C₁₋₆alkyl, wherein C₁₋₆alkyl is linear or        branched and is optionally substituted with 1–6 substituents        independently selected from 0–5 halogens and 0–1 phenyl, wherein        said optional phenyl substituent and said R⁵ when R5 is phenyl        or C₃₋₆cycloalkyl are optionally substituted with 1–5        substituents independently selected from halogen, OH, C₁₋₆alkyl,        and OC₁₋₆alkyl, said C₁₋₆alkyl and OC₁₋₆alkyl being linear or        branched and optionally substituted with 1–5 halogens; and    -   R⁷ is selected from the group consisting of        -   (1) H,        -   (2) C₁₋₆alkyl which is linear or branched and is optionally            substituted with 1–6 substituents independently selected            from 0–5 halogens and 0–1 substituents selected from            -   (a) phenyl,            -   (b) naphthyl,            -   (c) a 5 or 6-membered heterocyclic ring which may be                saturated or unsaturated comprising 1–4 heteroatoms                independently selected from N, S and O,            -   (d) an 8–10 membered bicyclic ring system which may be                saturated or unsaturated which comprises (a) two fused                heterocyclic rings, each heterocyclic ring having 1–4                heteroatoms independently selected from N, S and O,                or (b) a phenyl ring fused to a 5-or 6-membered                heterocycle having 1–3 heteroatoms selected from N, S                and O,            -   (e) C(═O)NR⁴R⁴,                wherein said phenyl, naphthyl, and R⁴ when R⁴ is phenyl                or C₃₋₆cycloalkyl are optionally substituted with 1–5                substituents independently selected from halogen, OH,                nitro, C₁₋₆alkyl, OC₁₋₆alkyl, and NHSO₂C₁₋₆alkyl, said                C₁₋₆alkyl, OC₁₋₆alkyl and NHSO₂C₁₋₆alkyl being linear or                branched and optionally substituted with 1–5 halogens,                and wherein said 5–6-membered heterocycle and 8–10                membered bicyclic ring system are optionally substituted                with 1–5 substituents independently selected from                halogen, oxo, OH, C₁₋₆alkyl, OC₁₋₆alkyl, and                NHSO₂C₁₋₆alkyl, said C₁₋₆alkyl, OC₁₋₆alkyl and                NHSO₂C₁₋₆alkyl being linear or branched and optionally                substituted with 1–5 halogens,        -   (3) Phenyl, which is optionally substituted with 1–5            substituents independently selected from halogen, OH,            C₁₋₆alkyl and OC₁₋₆alkyl, said C₁₋₆alkyl and OC₁₋₆alkyl            being linear or branched and optionally substituted with 1–5            halogens,        -   (4) a 5 or 6-membered heterocycle which may be saturated or            unsaturated comprising 1–4 heteroatoms independently            selected from N, S and O, wherein said heterocycle is            optionally substituted with 1–5 substituents independently            selected from halogen, oxo, OH, C₁₋₆alkyl and OC₁₋₆alkyl,            said C₁₋₆alkyl and OC₁₋₆alkyl being linear or branched and            optionally substituted with 1–5 halogens,        -   (5) an 8–10 membered bicyclic ring system which may be            saturated or unsaturated which comprises (a) two fused            heterocyclic rings, each heterocyclic ring having 1–4            heteroatoms selected from N, S and O, or (b) a 5- or            6-membered heterocycle having 1–3 heteroatoms selected from            N, S and O fused to a pheny ring, wherein said bicyclic ring            system is optionally substituted with 1–5 substituents            independently selected from halogen, oxo, OH, C₁₋₆alkyl and            OC₁₋₆alkyl, said C₁₋₆alkyl and OC₁₋₆alkyl being linear or            branched and optionally substituted with 1–5 halogens, and        -   (6) adamantyl, which is optionally substituted with 1–5            substituents independently selected from halogen, OH,            C₁₋₆alkyl and OC₁₋₆alkyl, said C₁₋₆alkyl and OC₁₋₆alkyl            being linear or branched and optionally substituted with 1–5            halogens;        -   (7) naphthyl, which is optionally substituted with 1–5            substituents independently selected from halogen, OH,            C₁₋₆alkyl and OC₁₋₆alkyl, said C₁₋₆alkyl and OC₁₋₆alkyl            being linear or branched and optionally substituted with 1–5            halogens; and        -   (8) a 5–6 membered cycloalkyl fused to a phenyl ring,            wherein said cycloalkyl may be saturated or unsaturated,            wherein said cycloalkyl and fused phenyl ring are optionally            substituted with 1–5 substituents independently selected            from halogen, OH, C₁₋₆alkyl and OC₁₋₆alkyl, said C₁₋₆alkyl            and OC₁₋₆alkyl being linear or branched and optionally            substituted with 1–5 halogens.

DETAILED DESCRIPTION OF THE INVENTION

The compounds having Formula I have numerous preferred embodiments,which are described below.

In embodiments of Formula I, R₂ is H. In other embodiments, R₃ is H. Inmany embodiments, R² and R³ are both H.

In preferred embodiments, Ar is phenyl, which is optionally substitutedas described above.

In other embodiments, R⁴ is H.

A preferred embodiment comprises compounds having formula I in which Qis selected from the group consisting of phenyl and CH₂phenyl,optionally substituted as described above.

Another embodiment comprises compounds having formula I as recited inclaim 1, wherein X is NR⁷, and R⁷ is CH², which is substituted with 1substituent selected from

-   -   (a) phenyl;    -   (b) naphthyl;    -   (c) a 5 or 6-membered heterocyclic ring which may be saturated        or unsaturated comprising 1–4 heteroatoms independently selected        from N, S and O;    -   (d) an 8–10 membered bicyclic ring system which may be saturated        or unsaturated which comprises (a) two fused heterocyclic rings,        each heterocyclic ring having 1–4 heteroatoms independently        selected from N, S and O, or (b) a phenyl ring fused to a 5-or        6-membered heterocycle having 1–3 heteroatoms selected from N, S        and O, and    -   (e) C(═O)NR⁴R⁴, wherein R⁴ is as previouly defined, and said        phenyl, naphthyl, and R⁴ when R⁴ is phenyl or C₃₋₆cycloalkyl are        optionally substituted with 1–5 substituents independently        selected from halogen, OH, C₁₋₆alkyl, OC₁₋₆alkyl, and        NHSO₂C₁₋₆alkyl, said C₁₋₆alkyl, OC₁₋₆alkyl and NHSO₂C₁₋₆alkyl        being linear or branched and optionally substituted with 1–5        halogens, and wherein said 5–6-membered heterocycle and 8–10        membered bicyclic ring system are optionally substituted with        1–5 substituents independently selected from halogen, oxo, OH,        C₁₋₆alkyl, OC₁₋₆alkyl, and NHSO₂C₁₋₆alkyl, said C₁₋₆alkyl,        OC₁₋₆alkyl and NHSO₂C₁₋₆alkyl being linear or branched and        optionally substituted with 1–5 halogens.

In the compounds described above, the 8–10 membered bicyclic ring systemis preferably selected from the group consisting of indole, indoline,benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole,benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline,dihydroquinazoline, dihydroquinoline, isoquinoline,tetrahydroisoquinoline, and dihydroisoquinoline, substituted asdescribed above. Indole is a preferred 8–10 membered bicyclic ringsystem.

Preferably, 5- or 6-membered heterocycles are selected from furan,thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole,pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole,thiazoline, isothiazole, isothiazoline, thiadiazole, thiadiazoline,tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine,pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran,imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine,piperidine, morpholine, tetrazole, triazole, triazolidine, andtetrazolidine. More preferred heterocycles include imidazole,morpholine, pyrazole, pyridine, tetrazole, thiazole and triazole.

Definitions

“Ac” is acetyl, which is CH₃C(O)—.

“Alkyl”, as well as other groups having the prefix “alk”, such as alkoxyor alkanoyl, means carbon chains which may be linear or branched orcombinations thereof, unless the carbon chain is defined otherwise.Examples of alkyl groups include methyl, ethyl, propyl, isopropyl,butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and thelike.

“Alkenyl” means carbon chains which contain at least one carbon-carbondouble bond, and which may be linear or branched or combinationsthereof. Examples of alkenyl include vinyl, allyl, isopropenyl,pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl,and the like.

“Alkynyl” means carbon chains which contain at least one carbon-carbontriple bond, and which may be linear or branched or combinationsthereof. Examples of alkynyl include ethynyl, propargyl,3-methyl-1-pentynyl, 2-heptynyl and the like.

“Cycloalkyl” means a mono- or bicyclic saturated carbocyclic ring havingfrom 3 to 10 carbon atoms. The term also can refer to a cycloalkyl ringfused to another ring such as an aromatic ring. Examples of cycloalkylinclude cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

“Aryl” (and “arylene”) means a mono- or polycyclic aromatic ring systemcontaining only carbon ring atoms. The term “aryl” also includes an arylgroup fused to a cycloalkyl or heterocycle, where aryl refers to thearomatic portion. The preferred aryls are phenyl and naphthyl. The mostpreferred aryl is phenyl.

“Heterocycle” means a saturated or unsaturated ring (including aromaticrings) containing at least one heteroatom selected from N, S and O(including SO and SO₂). Examples of heterocycles includetetrahydrofuran, piperazine, morpholine and sulfolane.

“Heteroaryl” (and heteroarylene) means an aromatic heterocycle thatcontains at least one ring heteroatom selected from N, O and S(including SO and SO₂). Heteroaryls can be fused to other heteroaryls orto other kinds of rings, such as aryls, cycloalkyls or heterocycles thatare not aromatic. Examples of monocyclic heteroaryls and heteroarylsfused to other rings (aryl or heteroaryl) include pyrrolyl, isoxazolyl,isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl,thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl,thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl,benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl,benzothiophenyl (including S-oxide and dioxide), furo(2,3-b)pyridyl,quinolyl, indolyl, isoquinolyl, dibenzofuran and the like.

“Halogen” includes fluorine, chlorine, bromine and iodine. Chlorine andfluorine are generally preferred.

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of the present invention and apharmaceutically acceptable carrier.

Optical Isomers-Diastereomers-Geometric Isomers-Tautomers

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Some of the compounds described herein may exist as tautomers, whichhave different points of attachment of hydrogen accompanied by one ormore double bond shifts. For example, a ketone and its enol form areketo-enol tautomers. The individual tautomers as well as mixturesthereof are encompassed with compounds of Formula I.

Formula I shows the structure of the class of compounds withoutpreferred stereochemistry. Formula Ia shows the preferred sterochemistryat the carbon atom that is attached to the amine group of the beta aminoacid from which these compounds are made.

Formula Ib shows the preferred sterochemistry at the carbon atom that isattached to the amine group of the beta amino acid from which thesecompounds are made and at the carbon atom attached to substituent Q.

The various substituent groups in the compounds of Formula Ia and Ib arethe same as those described previously for the compounds having FormulaI.

If desired, racemic mixtures of compounds of Formula I may be separatedso that the individual enantiomers are isolated. The separation can becarried out by methods well known in the art, such as the coupling of aracemic mixture of compounds of Formula I to an enantiomerically purecompound to form a diastereomeric mixture, followed by separation of theindividual diastereomers by standard methods, such as fractionalcrystallization or chromatography. The coupling reaction is often theformation of salts using an enantiomerically pure acid or base. Thediasteromeric derivatives may then be converted to the pure enantiomersby cleavage of the added chiral residue. The racemic mixture of thecompounds of Formula I can also be separated directly by chromatographicmethods utilizing chiral stationary phases, which methods are well knownin the art.

Alternatively, any enantiomer of a compound of the general Formula I maybe obtained by stereoselective synthesis using optically pure startingmaterials or reagents of known configuration. Such methods are wellknown in the art.

Compounds of Formula I may have more than one asymmetric center, as canbe seen in FIG. Ib. Such compounds may occur as mixtures ofdiasteromers, which can be separated into individual diasteromers bystandard methods, and the diastereomers can be further separated toindividual enantiomers as described above.

Salts

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts in thesolid form may exist in more than one crystal structure, and may also bein the form of hydrates. Salts derived from pharmaceutically acceptableorganic non-toxic bases include salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. Particularly preferred are citric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric, and tartaric acids.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Metabolites-Prodrugs

Metabolites of the compounds of this invention that are therapeuticallyactive and that are defined by Formula I or Ia are also within the scopeof this invention. Prodrugs are compounds that are converted totherapeutically active compounds as they are being administered to apatient or after they have been administered to a patient. Prodrugswhich are subsequently converted to a compound defined by Formula Iduring or after administration are also within the scope of theinvention, as are the active metabolites of the prodrug. A non-limitingexample of a prodrug of a compound having Formula I is a compound inwhich the amine group is functionalized with a group or groups that areremoved under physiological conditions after administration to amammalian patient to yield a compound having Formula I, or apharmaceutically acceptable salt thereof.

Utilities

DP-IV is a cell surface protein that has been implicated in a wide rangeof biological functions. It has a broad tissue distribution (intestine,kidney, liver, pancreas, placenta, thymus, spleen, epithelial cells,vascular endothelium, lymphoid and myeloid cells, serum), and distincttissue and cell-type expression levels. DP-IV is identical to the T cellactivation marker CD26, and it can cleave a number of immunoregulatory,endocrine, and neurological peptides in vitro. This has suggested apotential role for this peptidase in a variety of disease processes.

1. Type II Diabetes and Related Disorders

It is well established that the incretins GLP-1 and GIP are rapidlyinactivated in vivo by DP-IV. Studies with DP-IV^((−/−))-deficient miceand preliminary clinical trials indicate that DP-IV inhibition increasesthe steady state concentrations of GLP-1 and GIP, resulting in improvedglucose tolerance. By analogy to GLP-1 and GIP, it is likely that otherglucagon family peptides involved in glucose regulation are alsoinactivated by DP-IV (eg. PACAP, glucagon). Inactivation of thesepeptides by DP-IV may also play a role in glucose homeostasis.

The DP-IV inhibitors of this invention therefore may have utility in thetreatment of type II diabetes and in the treatment and prevention of thenumerous conditions that often accompany Type II diabetes, includingmetabolic syndrome X, reactive hypoglycemia, and diabetic dyslipidemia.Obesity, discussed below, is another condition that is often found withType II diabetes that may respond to treatment with the compounds ofthis invention.

The following diseases, disorders and conditions are related to Type 2diabetes, and therefore some or all of these may be treated, controlledor in some cases prevented, by treatment with the compounds of thisinvention: (1) hyperglycemia, (2) low glucose tolerance, (3) insulinresistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7)hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10)low HDL levels, (11) high LDL levels, (12) atherosclerosis and itssequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15)inflammatory bowel disease, including Crohn's disease and ulcerativecolitis, (16) other inflammatory conditions, (17) pancreatitis, (18)abdominal obesity, (19) neurodegenerative disease, (20) retinopathy,(21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), and other disorderswhere insulin resistance is a component.

2. Obesity

There is an expectation that DP-IV inhibitors may be useful for thetreatment of obesity. This expectation is based on the observedinhibitory effects on food intake and gastric emptying of GLP-1 andGLP-2. Exogenous administration of GLP-1 in humans significantlydecreases food intake and slows gastric emptying (Am. J. Physiol. 277,R910–R916 (1999)). ICV administration of GLP-1 in rats and mice also hasprofound effects on food intake (Nature Medicine 2, 1254–1258 (1996)).This inhibition of feeding is not observed in GLP-1R^((−/−)) mice,indicating that these effects are mediated through brain GLP-1receptors. By analogy to GLP-1, it is likely that GLP-2 is alsoregulated by DP-IV. ICV administration of GLP-2 also inhibits foodintake, analogous to the effects observed with GLP-1 (Nature Medicine 6,802–807 (2000)).

3. Growth Hormone Deficiency

DP-IV inhibition may be useful for the treatment of growth hormonedeficiency, based on the hypothesis that growth-hormone releasing factor(GRF), a peptide that stimulates release of growth hormone from theanterior pituitary, is cleaved by the DP-IV enzyme in vivo (WO00/56297). The following data provide evidence that GRF is an endogenoussubstrate: (1) GRF is efficiently cleaved in vitro to generate theinactive product GRF[3–44] (BBA 1122, 147–153 (1992)); (2) GRF israpidly degraded in plasma to GRF[3–44]; this is prevented by the DP-IVinhibitor diprotin A; and (3) GRF[344] is found in the plasma of a humanGRF transgenic pig (J. Clin. Invest. 83, 1533–1540 (1989)). Thus DP-IVinhibitors may be useful for the same spectrum of indications which havebeen considered in the case of Growth Hormone secretagogues.

4. Intestinal Injury

The potential for using DP-IV inhibitors for the treatment of intestinalinjury is suggested by the results of studies indicating thatglucagon-like peptide-2 (GLP-2), a likely endogenous substrate forDP-IV, may exhibit trophic effects on the intestinal epithelium(Regulatory Peptides 90, 27–32 (2000)). Administration of GLP-2 resultsin increased small bowel mass in rodents and attenuates intestinalinjury in rodent models of colitis and enteritis.

5. Immunosuppression

It has been suggested that DP-IV inhibition may be useful for modulationof the immune response, based upon studies implicating the DP-IV enzymein T cell activation and in chemokine processing, and efficacy of DP-IVinhibitors in in vivo models of disease. DP-IV has been shown to beidentical to CD26, a cell surface marker for activated immune cells. Theexpression of CD26 is regulated by the differentiation and activationstatus of immune cells. It is generally accepted that CD26 functions asa co-stimulatory molecule in in vitro models of T cell activation.

A number of chemokines contain proline in the penultimate position,presumably to protect them from degradation by non-specificaminopeptidases. Many of these have been shown to be processed in vitroby DP-IV. In several cases (RANTES, LD78-beta, MDC, eotaxin,SDF-1alpha), cleavage results in an altered activity in chemotaxis andsignaling assays. Receptor selectivity also appears to be modified insome cases (RANTES). Multiple N-terminally truncated forms of a numberof chemokines have been identified in in vitro cell culture systems,including the predicted products of DP-IV hydrolysis.

DP-IV inhibitors have been shown to be efficacious immunosupressants inanimal models of transplantation and arthritis. Prodipine(Pro-Pro-diphenyl-phosphonate), an irreversible inhibitor of DP-IV, wasshown to double cardiac allograft survival in rats from day 7 to day 14(Transplantation 63, 1495–1500 (1997)). DP-IV inhibitors have beentested in collagen and alkyldiamine-induced arthritis in rats and showeda statistically significant attenuation of hind paw swelling in thismodel (Int. J. Immunopharmacology 19, 15–24 (1997), Immunopharmacology40, 21–26 (1998)).

DP-IV is upregulated in a number of autoimmune diseases includingrheumatoid arthritis, multiple sclerosis, Graves' disease, andHashimoto's thyroiditis (Immunology Today 20, 367–375 (1999)).

6. HIV Infection

A number of chemokines which inhibit HIV cell entry are potentialsubstrates for DP-IV (Immunology Today 20, 367–375 (1999)). In the caseof SDF-1alpha, cleavage decreases antiviral activity (PNAS 95, 6331–6(1998)). Thus, stabilization of SDF-1alpha through inhibition of DP-IVwould be expected to decrease HIV infectivity.

7. Hematopoiesis

It has been suggested that DP-IV may be involved in hematopoiesis. ADP-IV inhibitor, Val-Boro-Pro, stimulates hematopoiesis in a mouse modelof cyclophosphamide-induced neutropenia (WO 99/56753).

8. Neuronal Disorders

A number of peptides implicated in a variety of neuronal processes arecleaved in vitro by DP-IV. A DP-IV inhibitor thus may have a therapeuticbenefit in the treatment of neuronal disorders. Endomorphin-2,beta-casomorphin, and substance P have all been shown to be in vitrosubstrates for DP-IV. In all cases, in vitro cleavage is highlyefficient, with k_(cat)/K_(m)˜10⁶M⁻¹s⁻¹ or greater. In an electric shockjump test model of analgesia in rats, a DP-IV inhibitor showed asignificant effect that was independent of the presence of exogenousendomorphin-2 (Brain Research 815, 278–286 (1999)).

9. Tumor Invasion and Metastasis

An increase or decrease in expression of several ectopeptidasesincluding DP-IV has been observed during the transformation of normalcells to a malignant phenotype (J. Exp. Med. 190, 301–305 (1999)). Up-or down-regulation of these proteins appears to be tissue and cell-typespecific. For example, increased CD26/DP-IV expression has been observedon T cell lymphoma, T cell acute lymphoblastic leukemia, cell-derivedthyroid carcinomas, basal cell carcinomas, and breast carcinomas. Thus,DP-IV inhibitors may have utility in the treatment of such carcinomas.

10. Benign Prostatic Hypertrophy

Increased DP-IV activity was noted in prostate tissue from patients withBPH (Eur. J. Clin. Chem. Clin. Biochem 30, 333–338 (1992)).

11. Sperm Motility/Male Contraception

In seminal fluid, prostatosomes, prostate derived organelles importantfor sperm motility, possess very high levels of DP-IV activity (Eur. J.Clin. Chem. Clin. Biochem 30, 333–338 (1992)).

12. Gingivitis

DP-IV activity was found in gingival crevicular fluid and in somestudies correlated with periodontal disease severity (Arch. Oral Biol.37, 167–173 (1992)).

13. Osteoporosis

GIP receptors are present in osteoblasts.

It is therefore anticipated that the compounds of Formula I, Ia and Ibmay have utility in treating one or more of the following conditions ordiseases: (1) hyperglycemia, (2) low glucose tolerance, (3) insulinresistance, (4) obesity, (5) lipid disorders, (6) dyslipidemia, (7)hyperlipidemia, (8) hypertriglyceridemia, (9) hypercholesterolemia, (10)low HDL levels, (11) high LDL levels, (12) atherosclerosis and itssequelae, (13) vascular restenosis, (14) irritable bowel syndrome, (15)inflammatory bowel disease, including Crohn's disease and ulcerativecolitis, (16) other inflammatory conditions, (17) pancreatitis, (18)abdominal obesity, (19) neurodegenerative disease, (20) retinopathy,(21) nephropathy, (22) neuropathy, (23) Syndrome X, (24) ovarianhyperandrogenism (polycystic ovarian syndrome), (25) Type II diabetes,(26) growth hormone deficiency, (27) neutropenia, (28) neuronaldisorders, (29) tumor metastasis, (30) benign prostatic hypertrophy,(32) gingivitis, (33) hypertension, (34) osteoporosis, and otherconditions that may be treated by inhibition of DP-IV, wherein saidtreatment comprises the administration to a human or mammalian patientof a therapeutically effective amount of a compound having Formula I,including pharmaceutically acceptable salts and prodrugs.

Combination Therapy

Compounds of Formula I may be used in combination with one or more otherdrugs in the treatment, prevention, suppression or amelioration ofdiseases or conditions for which compounds of Formula I or the otherdrugs may have utility, where the combination of the drugs together aresafer or more effective than either drug alone. Such other drug(s) maybe administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of Formula I. When acompound of Formula I is used contemporaneously with one or more otherdrugs, a pharmaceutical composition in unit dosage form containing suchother drugs and the compound of Formula I is preferred. However, thecombination therapy may also include therapies in which the compound ofFormula I and one or more other drugs are administered on differentoverlapping schedules. It is also contemplated that when used incombination with one or more other active ingredients, the compounds ofthe present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof Formula I.

Examples of other active ingredients that may be administered incombination with a compound of Formula I, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

(a) other dipeptidyl peptidase IV (DP-IV) inhibitors;

(b) insulin sensitizers including (i) PPARγ agonists such as theglitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555,rosiglitazone, and the like) and other PPAR ligands, including PPARα/γdual agonists, such as KRP-297, and PPARα agonists such as fenofibricacid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),(ii) biguanides such as metformin and phenformin, and (iii) proteintyrosine phosphatase-1B (PIP-1B) inhibitors;

(c) insulin or insulin mimetics;

(d) sulfonylureas and other insulin secretagogues such as tolbutamideand glipizide, meglitinide, and related materials;

(e) α-glucosidase inhibitors (such as acarbose);

(f) glucagon receptor antagonists such as those disclosed in WO98/04528, WO 99/01423, WO 00/39088, and WO 00/69810;

(g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists such as thosedisclosed in WO00/42026 and WO/59887;

(h) GIP, GIP mimetics such as those disclosed in WO00/58360, and GIPreceptor agonists;

(i) PACAP, PACAP mimetics, and PACAP receptor 3 agonists such as thosedisclosed in WO 01/23420;

(j) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors(lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin,rivastatin, itavastatin, rosuvastatin, and other statins), (ii)sequestrants (cholestyramine, colestipol, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) nicotinyl alcohol,nicotinic acid or a salt thereof, (iv) PPARα agonists such as fenofibricacid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate),(v) PPARα/γ dual agonists, such as KRP-297, (vi) inhibitors ofcholesterol absorption, such as for example ezetimibe andbeta-sitosterol, (vii) acyl CoA:cholesterol acyltransferase inhibitors,such as for example avasimibe, and (viii) anti-oxidants, such asprobucol;

(k) PPARδ agonists, such as those disclosed in WO97/28149;

(l) antiobesity compounds such as fenfluramine, dexfenfluramine,phentermine, sibutramine, orlistat, neuropeptide Y5 inhibitors, andβ₃adrenergic receptor agonists;

(m) an ileal bile acid transporter inhibitor; and

(n) agents intended for use in inflammatory conditions such as aspirin,non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, andcyclo-oxygenase 2 selective inhibitors.

The above combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds. Non-limiting examples include combinationsof compounds having Formula I with two or more active compounds selectedfrom biguanides, sulfonylureas, HMG-CoA reductase inhibitors, PPARagonists, PTP-1B inhibitors, other DP-IV inhibitors, and anti-obesitycompounds.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds ofFormula I are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating or preventing diabetes mellitus and/or hyperglycemia orhypertriglyceridemia or other diseases for which compounds of Formula Iare indicated, generally satisfactory results are obtained when thecompounds of the present invention are administered at a daily dosage offrom about 0.1 milligram to about 100 milligram per kilogram of animalbody weight, preferably given as a single daily dose or in divided dosestwo to six times a day, or in sustained release form. For most largemammals, the total daily dosage is from about 1.0 milligrams to about1000 milligrams, preferably from about 1 milligrams to about 50milligrams. In the case of a 70 kg adult human, the total daily dosewill generally be from about 7 milligrams to about 350 milligrams. Thisdosage regimen may be adjusted to provide the optimal therapeuticresponse.

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceuticalcompositions which comprise a compound of Formula I and apharmaceutically acceptable carrier. The pharmaceutical compositions ofthe present invention comprise a compound of Formula I or apharmaceutically acceptable salt or prodrug thereof as an activeingredient, as well as a pharmaceutically acceptable carrier. Optionallyother therapeutic ingredients or other DP-IV inhibitors, or both, may beincluded in the pharmaceutical compositions as discussed previously. Theterm “pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids, includinginorganic bases or acids and organic bases or acids.

The compositions include compositions suitable for oral, rectal,topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, hard and soft capsules and tablets, with the solidoral preparations being preferred over the liquid preparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of formula I may also be administered parenterally. Solutionsor suspensions of these active compounds can be prepared in watersuitably mixed with a surfactant such as hydroxy-propylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Assays: Measurement of Inhibition Constants

Inhibition constants were determined as follows. A continuousfluorometric assay was developed with the substrate Gly-Pro-AMC, whichis cleaved by DP-IV to release the fluorescent AMC leaving group. Thekinetic parameters that describe this reaction are as follows: K_(m)=50μM; k_(cat)=75s⁻¹; k_(cat)/K_(m)=1.5×10⁶ M⁻¹s⁻¹. A typical reactioncontains approximately 50 pM enzyme, 50 μM Gly-Pro-AMC, and buffer (100mM HEPES, pH 7.5, 0.1 mg/ml BSA) in a total reaction volume of 100 μl.Liberation of AMC is monitored continuously in a 96-well platefluorometer using an excitation wavelength of 360 nm and an emissionwavelength of 460 nm. Under these conditions, approximately 0.8 μM AMCis produced in 30 minutes at 25 degrees C. Unless otherwise indicated,the enzyme used in these studies was soluble (transmembrane domain andcytoplasmic extension excluded) human protein produced in a baculovirusexpression system (Bac-To-Bac, Gibco BRL). The kinetic constants forhydrolysis of Gly-Pro-AMC and GLP-1 were found to be in accord withliterature values for the native enzyme.

The compounds described herein generally have inhibition constants ofless than 10 μM. Preferred compounds have inhibition constants of lessthan 1 μM. Highly preferred compounds have inhibition constants of lessthan 300 nM.

To measure the dissociation constants for compounds, solutions ofinhibitor in DMSO were added to reactions containing enzyme andsubstrate (final DMSO concentration is 1%). All experiments wereconducted at room temperature using the standard reaction conditionsdescribed above. To determine the dissociation constants (K_(i)),reaction rates were fit by non-linear regression to the Michaelis-Mentonequation for competitive inhibition. The errors in reproducing thedissociation constants are typically less than two-fold.

Synthetic Schemes

The compounds (I) of the present invention can be prepared from betaamino acid intermediates such as those of formula II and substitutedheterocyclic intermediates such as those of formula III, using standardpeptide coupling conditions followed by deprotection. The preparation ofthese intermediates is described in the following schemes.

where Ar, R², R³, Q, and X are as defined above and P is a suitablenitrogen protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl, or 9-fluorenylmethoxycarbonyl.

Compounds IIa, where R³ is hydrogen, are commercially available, knownin the literature or may be conveniently prepared by a variety ofmethods familiar to those skilled in the art. One common route isillustrated in Scheme 1. Acid 1, which may be commercially available orreadily prepared from the corresponding amino acid by protection using,for example, N-(9-fluorenylmethoxycarbonyloxy)succinimide, is treatedwith isobutylchloroformate and diazomethane using a base such astriethylamine. The resultant diazoketone is then treated with silverbenzoate in aqueous dioxane and may be subjected to sonication followingthe procedure of Sewald et al., Synthesis, 837 (1997) in order toprovide the beta amino acid IIa. As will be understood by those skilledin the art, for the preparation of enantiomerically pure beta aminoacids II, enantiomerically pure alpha amino acids 1 may be used.Alternate routes to these compounds can be found in the followingreviews: E. Juaristi, Enantioselective Synthesis of β-Amino Acids, Ed.,Wiley-VCH, New York: 1997, Juaristi et al., Aldrichimica Acta, 27, 3(1994), Cole et al., Tetrahedron, 32, 9517 (1994).

Compounds IIb, where R³ is alkyl, may be conveniently prepared asdescribed in Podlech et al., Liebigs Ann., 1217 (1995) and illustratedin Scheme 2. An amino acid such as IIa, from Scheme 1, can be esterifiedeither by treatment with a mineral acid such as hydrochloric acid in analcoholic solvent, for example methanol, at temperatures of 0 to 60° C.for 2 to 48 hours, or by using a coupling agent such asdicyclohexylcarbodiimide and an alcohol such as methanol or benzylalcohol in dichloromethane. The resultant ester can then be deprotonatedwith a hindered base such as lithium diispropylamide at a temperature of−80 to −60° C. and alkylated by addition of an alkyl halide such asmethyl or ethyl iodide. Removal of the ester can then be achieved bytreatment with a base such as aqueous lithium hydroxide in a solventsuch as THF, methanol or mixture of similar solvents. In the case of abenzyl ester, removal is achieved by catalytic hydrogenation using apalladium catalyst in a solvent such as methanol, ethyl acetate ormixture of such solvents.

Compounds III are commercially available, known in the literature or maybe conveniently prepared by a variety of methods familiar to thoseskilled in the art. One common route to the intermediates used belowwhen X═O is described in Shaw et al., Synthetic Commun., 1777 (1997) andillustrated in Scheme 3. A glycinol derivative 2 is coupled with2-chloroacetyl chloride in a solvent such as dichloromethane or THF inthe presence of a base such as aqueous sodium hydroxide. Cyclization of3 is then effected by deprotonation of the alcohol with sodium hydridein THF at ambient temperature, followed by reduction of the amide with ahydride reducing agent such as lithium aluminum hydride in a polarsolvent such as THF at 0 to 50° C. for 2 to 24 hours, to give amineIIIa.

A convenient route for the preparation of amines III when X is NR⁷ isillustrated in Scheme 4. A piperazine 4, which is suitably protected,for example as its tert-butyl or benzyl carbamate derivative, can beelaborated by alkylation of the piperazine nitrogen. This can beeffected by treatment with an alkyl halide, in one examplealpha-chloro-3-nitroacetanilide is used, in a polar solvent such asdimethylformamide (DMF), and a hindered base, for examplediiospropylethylamine (DIEA), for 2 to 24 hours. The protecting group isthen removed with, for example, trifluoroacetic acid in the case of Boc,or hydrobromic acid in acetic acid in the case of Cbz to give thedesired amine IIIb.

Compounds 4 from Scheme 4 are commercially available, known in theliterature or may be conveniently prepared by a variety of methodsfamiliar to those skilled in the art. In some cases, the couplingproduct 5 from the reactions described in Scheme 4 may be furthermodified, for example, by the manipulation of substituents on R⁷. Thesemanipulations may include, but are not limited to, reduction, oxidation,alkylation, acylation, and hydrolysis reactions which are commonly knownto those skilled in the art. In one example, the nitro group in 5 isreduced using, for example Raney nickel and hydrazine in a polar solventsuch as methanol at 25 to 60° C. for 0.5 to 3 hours to give an anilinewhich may be acylated using, for example, methanesulfonyl chloride, in asolvent such as methylene chloride and a base, generally pyridine ortriethylamine, for 3 to 48 hours at ambient temperature. Deprotection asdescribed above gives the desired amine IIIc.

An alternate route to compounds III, is described in Kiely et al., Org.Preps. and Procedures Int., 22, 761, (1990) and illustrated in Scheme 5.An amino acid 6, which is suitably protected as, for example, itstert-butyl carbamate is coupled with an appropriate glycine derivative,such as N-benzylglycine ethyl ester, using a standard coupling reagentsuch as dicyclohexylcarbodiimide (DCC) or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) in a solvent such asdichloromethane for 1 to 16 hours. The reaction may contain a catalystsuch as N,N-dimethylamino-4-pyridine. The carbamate protecting group isthen removed with, for example, hydrogen chloride in a solvent such asethyl acetate at 0 to 25° C. for 3 to 24 hours, followed by an aqueouswork up of the reaction using an inorganic base such as sodiumbicarbonate to facilitate cyclization affording the diketopiperazine 7.Reduction to the piperazine IIId can be effected with a hydride reducingagent such as lithium aluminum hydride or borane-THF complex in a polaraprotic solvent generally tetrahydrofuran at 0 to 50° C. for 2 to 24hours. In some cases, the reduction product IIId from the reactionsdescribed in Scheme 5 may be further modified, for example, by themanipulation of substituents on Q. These manipulations may include, butare not limited to, reduction, oxidation, alkylation, acylation, andhydrolysis reactions which are commonly known to those skilled in theart.

Intermediates II and III are coupled under standard peptide couplingconditions, for example, using1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),1-hydroxybenzotriazole (HOBt), and a base, generallydiisopropylethylamine, in a solvent such as N,N-dimethylformamide (DMF)or methylene chloride for 3 to 48 hours at ambient temperature toprovide intermediate 8 as shown in Scheme 6. The protecting group isthen removed with, for example, trifluoroacetic acid in the case of Bocto give compound I. The product is purified from unwanted side productsby recrystallization, trituration, preparative thin layerchromatography, flash chromatography on silica gel as described by W. C.Still et al, J. Org. Chem., 43, 2923 (1978), or HPLC. Compounds whichare purified by HPLC may be isolated as the corresponding salt.Purification of intermediates is achieved in the same manner.

In some cases the intermediate 8 from the coupling reaction described inScheme 6 may be further modified before removal of the protecting group,for example, by manipulation of substituents on R², R³, Q or R⁷ (whenX=NR⁷). These manipulations may include, but are not limited to,reduction, oxidation, alkylation, acylation, and hydrolysis reactionswhich are commonly known to those skilled in the art. One such exampleis illustrated in Scheme 7. Compound 8 (X=NR⁷=NBn), which is prepared asoutlined in Scheme 6 from Intermediate IIId, is reduced by catalytichydrogenation using a palladium catalyst in a solvent such as methanol,ethyl acetate or a mixture of solvents to give amine 9. Alkylation ofthis amine with a group R⁷ can be achieved as described in Scheme 4 oras shown in Scheme 7, by reaction with an aldehyde, for exampleparaformaldehyde, in a chlorinated solvent such as 1,2-dichloroethanewith a reducing agent, generally sodium triacetoxyborohydride in thepresence of a dehydrating agent such as 4A molecular sieves at ambienttemperature for 1 to 24 hours. Protecting group removal is then achievedas described above to give amine Ic. Alternatively amine 9 can bearylated using chemistry known to those skilled in the art and describedin Wolfe et. al., J. Org. Chem., 65, 1158 (2000). In addition, amine 9may be deprotected directly, as described above, to provide Ia (R⁷=H).

Another such example is illustrated in Scheme 8. Compound 8 is preparedas described in Scheme 6 using a beta amino acid II where R³=OP¹ (P¹being a suitable protecting group such as tert-butyldimethylsilyl). Suchamino acids are commercially available, known in the literature or maybe conveniently prepared by a variety of methods familiar to thoseskilled in the art. Compound 8 is then treated with a fluoride sourcesuch as tetrabutylammonium fluoride in a solvent, normally THF, for 2 to48 hours to release the alcohol 10. This is then subsequently reactedwith a fluorinating agent such as [bis(2-methoxyethyl)amino]sulfurtrifluoride followed by removal of the protecting group as previouslydescribed to give the fluoro analog Id.

EXAMPLES

The following examples are provided so that the invention might be morefully understood. These examples are illustrative only and should not beconstrued as limiting the invention in any way.

Example 1

Step A. Methyl(4-{2-[(3-nitrophenyl)amino]-2-oxoethyl}piperazin-2-yl)acetate. To asolution of 1.5 g (5.83 mmol) of methyl (RS)-tert-butyl2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate and 2.5 g (11.66 mmol)of alpha-chloro-3-nitroacetanilide in 50 mL of DMF was added 4.06 mL(23.32 mmol) of diisopropylethylamine (DIEA), and stirring was continuedat ambient temperature for 16 h. The reaction was diluted with ethylacetate and washed sequentially with water and brine, and dried overmagnesium sulfate to give 7 g of a crude oil. Purification by flashchromatography (silica gel, 40 to 50% ethyl acetate in hexanes) yielded3.9 g of protected piperazine. This was dissolved in 100 mL of a 1:1mixture of methylene chloride:trifluoroacetic acid and the reaction wasstirred for 2 h, before concentration in vacuo. The residual oil wasdissolved in methylene chloride and concentrated to remove excesstrifluoroacetic acid. Neutralization was effected by adding a solutionof 10% concentrated ammonium hydroxide in methanol and concentration invacuo, followed by dissolving the residue in ethyl acetate and washingsequentially with saturated sodium bicarbonate solution, water, andbrine. The solution was dried over magnesium sulfate and concentrated invacuo to yield 2.87 g of the title compound.¹H NMR (400 MHz, CD₃OD) δ8.67 (s, 1H), 7.98–7.95 (m, 2H), 7.57 (t, 1H, J=8 Hz), 3.63 (s, 3H),3.60–3.39 (m, 4H), 3.37–3.10 (m, 4H), 2.98–2.90 (m, 1H), 2.82–2.62 (m,2H).

Step B. Methyl{1-[(3R)-3-amino-4-(3,4-difluorophenyl)butanoyl]-4-[2-({3-[(methyl-sulfonyl)amino]phenyl}amino)-2-oxoethyl]piperazin-2-yl}acetate,bistrifluoroacetate salt. To a solution of 0.298 g (0.889 mmol) ofmethyl (4-{2-[(3-nitrophenyl)amino]-2-oxoethyl}piperazin-2-yl)acetate in5 mL of dimethylformamide (DMF) was added 0.336 g (1.07 mmol) of(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2-fluorophenyl)butanoic acid,0.205 g (1.07 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride (EDC), 180 mg (1.33 mmol) of 1-hydroxybenzotriazolehydrate (HOBT), and 0.386 mL (2.2 mmol) of diisopropylethylamine (DIEA).The mixture was stirred for 16 h and diluted with ethyl acetate. Theorganic phase was washed sequentially with water, saturated aqueoussodium bicarbonate solution, water, brine, dried over magnesium sulfateand the solvent removed in vacuo to yield crude product. This wasimmediately dissolved in 10 mL of methanol, palladium hydroxide onactivated charcoal (˜50 mg) was added, and the mixture was stirred undera balloon of hydrogen for 0.5 h. The reaction was diluted with methanol,filtered through a pad of Celite, and concentrated in vacuo.Purification using preparative thin layer chromatography (TLC) (silicagel, 4.5:0.5:95 methanol:concentrated ammonium hydroxide:methylenechloride) afforded 425 mg of the desired aniline. A portion (60 mg, 0.1mmol), of this was dissolved in 3 mL of methylene chloride and 0.1 mL(1.2 mmol) of pyridine and 0.0116 mL (0.15 mmol) of methanesulfonylchloride were added. The reaction was stirred for 16 h beforeconcentration in vacuo and purification by preparative TLC (silica gel,4.5:0.5:95 methanol:concentrated ammonium hydroxide:methylene chloride)to afford 54 mg of the title compound as its tert butyl carbamate.

A portion (15 mg) of this material was deprotected, as described in StepA above, to give the title compound which was isolated as itsbistrifluoroacetate salt and not purified further. ¹H NMR (400 MHz,CD₃OD) δ 7.63 (s, 1H), 7.38–7.21 (m, 4H), 7.13–7.07 (m, 1H), 6.99 (d,1H, J=8 Hz), 3.95–3.50 (m, 11H), 3.30–3.18 (m, 1H), 3.10–2.95 (m, 3H),2.98 (s, 3H), 2.90–2.79 (m, 2H), 2.75–2.60 (m, 2H).

Example 2

{1-[(3R)-3-Amino-4-(3,4-difluorophenyl)butanoyl]-4-[2-({3-[(methylsulfonyl)amino]-phenyl}-amino)-2-oxoethyl]piperazin-2-yl}aceticacid, bistrifluoroacetate salt. To a solution of 35 mg (0.051 mmol) ofthe tert-butyl carbamate of methyl{1-[(3R)-3-amino-4-(3,4-difluorophenyl)butanoyl]-4-[2-({3-[(methyl-sulfonyl)amino]phenyl}amino)-2-oxoethyl]piperazin-2-yl}acetatein 1.5 mL of THF was added 10 mg (0.255 mmol) of lithium hydroxide in0.5 mL of water and the reaction was stirred for 16 h and concentratedin vacuo. The aqueous solution was acidified with 2N hydrochloric acidand extracted three times with ethyl acetate. The combined organic phasewas washed with brine, dried over magnesium sulfate, and concentrated invacuo to give 38 mg of product which was deprotected as described inExample 1, Step A, to give the title compound which was isolated as itsbistrifluoroacetate salt and not purified further. ¹H NMR (400 MHz,CD₃OD) δ 7.64 (s, 1H), 7.37–7.21 (m, 4H), 7.12–7.08 (m, 1H), 6.99 (d,1H, J=8 Hz), 4.11–3.55 (m, 8H), 3.42–3.08 (m, 2H), 3.00–2.93 (m, 2H),2.98 (s, 3H), 2.92–2.80 (m, 2H), 2.75–2.63 (m, 2H).

Example 3

(2R)-4-[(3R)-3-Benzylmorpholin-4-yl]-1-(2-fluorophenyl)-4-oxobutan-2-amine,trifluoroacetate salt. To a solution of 16.5 mg (0.093 mmol) of(R)-3-(phenylmethyl)morpholine (prepared as described in Shawe et al;Synthetic Communications, 1777–1782, 1997) in 1 mL of dimethylformamide(DMF) was added 33 mg (0.11 mmol) of(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2-fluorophenyl)butanoic acid,21.3 mg (0.11 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (EDC), 18.9 mg (0.14 mmol) of 1-hydroxybenzotriazolehydrate (HOBT), and 0.041 mL (0.23 mmol) of diisopropylethylamine(DIEA). The mixture was stirred for 16 h and diluted with ethyl acetate.The organic phase was washed sequentially with water, saturated aqueoussodium bicarbonate solution, water, and brine, and dried over magnesiumsulfate. The solvent was removed in vacuo and the compound purified bypreparative TLC (silica gel, 50% ethyl acetate in hexanes) to give theproduct which was deprotected as described in Example 1, Step A, to givethe title compound and isolated as its trifluoroacetate salt withoutfurther purification. ¹H NMR (400 MHz, CD₃OD) δ 7.39–7.12 (m, 9H),4.62–4.58 (m, 0.5H), 4.28 (d, 0.5H, J=15 Hz), 3.99–3.90 (m, 1H),3.78–3.59 (m, 2.51), 3.51–3.39 (m, 3H), 3.27–3.19 (m, 0.5H), 3.05–2.49(m, 5.5H), 1.8 (dd, 0.5H, J=8, 20 Hz).

Example 4

(2R)-4-[(3R)-3-Benzylmorpholin-4-yl]-1-(3,4-difluorophenyl)-4-oxobutan-2-amine,trifluoroacetate salt. In a manner identical to that described forExample 3, the title compound was prepared. ¹H NMR (400 MHz, CD₃OD) δ7.33–7.12 (m, 7H), 7.05–6.99 (m, 1H), 4.62–4.60 (m, 0.5H), 4.28 (d,0.5H, J=15 Hz), 3.99–3.90 (m, 1H), 3.83–3.72 (m, 1.5H), 3.69–3.58 (m,1H), 3.56–3.40 (m, 3H), 3.27–3.19 (m, 0.5H), 3.13–2.99 (m, 1.5H),2.92–2.78 (m, 2H), 2.77–2.68 (1H), 2.65–2.60 (m, 0.5H), 2.53–2.48 (m,0.5H), 1.78 (dd, 0.5H, J=8.20 Hz).

Example 5

Step A. Benzyl2-benzyl-4-{2-[(3-nitrophenyl)amino]-2-oxoethyl}piperazine-1-carboxylate.To a solution of 3.0 g (10.9 mmol) of (RS)-tert-butyl2-benzylpiperazine-1-carboxylate in 30 mL of methylene chloride at 0° C.was added 2.3 mL (16.5 mmol) of triethylamine and 1.7 mL (11.9 mmol) ofbenzyl chloroformate. The resultant mixture was stirred at ambienttemperature for 16 h and an additional 0.4 mL (2.8 mmol) of benzylchloroformate was added. After stirring for a further 2 h, the reactionwas partitioned between methylene chloride and water. The organic layerwas washed sequentially with dilute hydrochloric acid, saturated sodiumbicarbonate solution, and brine, dried over magnesium sulfate, andconcentrated in vacuo to give 4-benzyl 1-tert-butyl2-benzylpiperazine-1,4-dicarboxylate. The tert butyl carbamate wasdeprotected as described in Example 1, Step A to give 2.9 g of the freeamine. A portion (1.5 g, 4.8 mmol), of this material was coupled with1.6 g (7.5 mmol) of alpha-chloro-3-nitroacetanilide as described inExample 1, Step A, to give 1.3 g of the title compound as an off-whitefoamy solid. ¹H NMR (400 MHz, CD₃OD) δ 8.70 (s, 1H), 7.99 (d, 1H, J=8Hz), 7.96 (d, 1H, J=8 Hz), 5.58 (t, 1H, J=8 Hz), 7.36–7.05 (m, 10H),5.00 (bs, 2H), 4.38–4.31 (m, 1H), 3.99 (d, 1H, J=16 Hz), 3.48 (td, 1H,J=16,2 Hz), 3.22–2.95 (m, 5H), 2.80 (d, 1H, J=14 Hz), 2.33–2.20 (m, 2H).

Step B.2-(3-Benylpiperazin-1yl)-N-{3-[(methylsulfonyl)amino]phenyl}acetamide.To a solution of 1.3 g (2.66 mmol) of benzyl2-benzyl-4-{2-[(3-nitrophenyl)amino]-2-oxoethyl}piperazine-1-carboxylatein 50 mL of a 1:1 mixture of methanol :1,2-dichloroethane was added0.415 mL of hydrazine hydrate and 1.5 mL of a 50% suspension of Raneynickel in water. The reaction was stirred at 60° C. for 45 min, cooled,filtered through a Celite pad, washed with methanol, and concentrated invacuo to yield 1.1 g of a foamy white solid which was used withoutfurther purification. A portion (0.51 g, 1.1 mmol), of this material wasconverted to the methanesulfonamide using the procedure described inExample 1, Step B, to yield 0.5 g of2-(3-benzylpiperazin-1yl)-N-{3-[(methylsulfonyl)amino]phenyl}acetamideas its benzyl carbamate. The product was dissolved in 15 mL of methanol,palladium hydroxide on activated carbon (˜200 mg) was added, and themixture was stirred under a balloon of hydrogen for 24 h. The reactionwas diluted with methanol, filtered through a pad of Celite, andconcentrated in vacuo to afford 337 mg of2-(3-benzylpiperazin-1yl)-N-{3-[(methylsulfonyl)-amino]phenyl}acetamideas a fluffy white solid which was used without further purification. ¹HNMR (400 MHz, CD₃OD) δ 7.58 (s, 1H), 7.30–7.18 (m, 7H), 7.00–6.98 (m,1H), 3.15–3.05 (m, 3H), 3.02–2.59 (m, 7H), 2.77–2.62 (m, 2H), 2.32–2.25(m, 1H), 2.02 (t, 1H, J=14 Hz).

Step C.2-{(3R)-4-[(3R)-3-Amino-4-(2-fluorophenyl)butanoyl]-3-benzylpiperazin-1-yl}-N-{3-[(methylsulfonyl)amino]phenyl}acetamide,bistrifluoroacetate salt. To a solution of 30 mg (0.075 mmol) of2-(3-benzylpiperazin-1yl)-N-{3-[(methylsulfonyl)-amino]phenyl}acetamidein 3 mL of dimethylformamide (DMF) was added 25 mg (0.084 mmol) of(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2-fluorophenyl)butanoic acid, 16mg (0.083 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride (EDC), 14 mg (0.104 mmol) of 1-hydroxybenzotriazolehydrate (HOBT), and 0.030 mL (0.172 mmol) of diisopropylethylamine(DIEA). The mixture was stirred for 16 h and diluted with ethyl acetate.The organic phase was washed with water, saturated aqueous sodiumbicarbonate solution, water, brine, dried over magnesium sulfate. Thesolvent was removed in vacuo and the product purified twice bypreparative TLC (silica gel, 5% methanol in methylene chloride) to givethe title compound as its tert-butyl carbamate. The product wasdeprotected as described in Example 1, Step A to give 32.9 mg of theproduct as a 1:1 mixture of diastereomers. Separation of the isomers waseffected using reverse phase preparative HPLC (27% acetonitrile in watercontaining 0.1% trifluoroacetic acid) to give 8.3 mg of the titlecompound. ¹H NMR (400 MHz, CD₃OD) δ 7.70 (s, 1H), 7.40–7.10 (m, 11H),6.98 (d, 1H, J=7.4 Hz), 4.97–4.90 (m, 0.5H), 4.63 (d, 0.5H, J=15 Hz),4.16–4.08 (m, 0.5H), 3.87–3.79 (m, 1.5H), 3.77–3.56 (m, 3H), 3.40–3.10(m, 3H), 3.09–2.58 (m, 9.5H), 1.83 (dd, 0.5H, J=8.4, 16 Hz). Continuedelution provided 9.6 mg of2-{(3S)-4-[(3R)-3-amino-4-(2-fluorophenyl)-butanoyl]-3-benzylpiperazin-1-yl}-N-{3-[(methylsulfonyl)amino]phenyl}acetamide,bistrifluoroacetate salt. ¹H NMR (400 MHz, CD₃OD) δ 7.71 (s, 1H),7.42–7.06 (m, 11H), 6.98 (d, 1H, J=7.8 Hz), 4.98–4.90 (m, 0.5H), 4.63(d, 0.5H, J=15 Hz), 4.20–4.13 (m, 0.5H), 3.82–3.79 (m, 1.5H), 3.75–3.58(m, 1.5H), 3.42–3.10 (m, 4.5H), 3.09–2.40 (m, 9.5H), 1.75 (dd, 0.5H,J=2.16 Hz).

Example 6

Step A. (R)-1,3-Dibenzylpiperazine. To a solution of 1.0 g (3.8 mmol) ofN—BOC-D-phenyl alanine and 0.875 g (4.53 mmol) of N-benzylglycine ethylester in 15 mL of methylene chloride was added 0.863 g (4.5 mmol) of1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and acatalytic amount of N,N-dimethyl-4-aminopyridine. The reaction wasstirred at ambient temperature for 16 h, concentrated in vacuo. Theresidue was suspended in ethyl acetate, and washed sequentially withdilute hydrochloric acid, saturated sodium bicarbonate solution, water,and brine, dried over magnesium sulfate, and concentrated in vacuo togive 1.21 g of coupled material as a white solid. This amide wassuspended in 20 mL of ethyl acetate and cooled to 0° C. Hydrogenchloride was bubbled into the solution for 5 min and the reaction wasstirred at ambient temperature for 2 h before concentration in vacuo.The residue was partitioned between methylene chloride and saturatedsodium bicarbonate solution. The organic phase was washed sequentiallywith saturated sodium bicarbonate solution, and brine, dried overmagnesium sulfate, and concentrated in vacuo to give 0.78 g of cyclicmaterial. This material was added portionwise to a suspension of 0.485 gof lithium aluminum hydride in 20 mL of tetrahydrofuran at 0° C., andthe reaction mixture was heated under reflux for 16 h. After cooling,0.485 mL of water, 0.485 mL of 2N aqueous sodium hydroxide solution, and1.5 mL of water were sequentially added in a dropwise manner. The whiteprecipitate was removed by filtration through a Celite pad, and thefiltrate was concentrated in vacuo. The crude material was suspended inethyl acetate and washed with brine, dried over magnesium sulfate andreconcentrated to give 718 mg of (R)-1,3-dibenzylpiperazine which wasused without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.19(m, 10H), 3.60–3.45 (m 2H), 3.20–3.15 (m, 1H), 3.09–3.05 (m, 1H),3.00–2.75 (m, 5H), 2.33–2.26 (m, 1H), 2.17–2.10 (m, 1H).

Step B.(2R)-4-[(2R)-2,4-Dibenzylpiperazin-1-yl]-1-(2-fluorophenyl)-4-oxobutan-2-amine,bistrifluoracetate salt (R)-1,3-Dibenzylpiperazine (200 mg, 0.75 mmol)of was coupled to 357 mg (1.2 mmol) of(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2-fluorophenyl)butanoic acidusing the procedure outlined in Example 3 to give 471 mg of the finalproduct as its tert-butyl carbamate.

A portion of the material was purified by preparative TLC (silica gel,50% ethyl acetate in hexanes), and then deprotected as described inExample 1, Step A, to give the title compound which was isolated as itsbistrifluoroacetate salt and not purified further. ¹H NMR (400 MHz,CD₃OD) δ 7.58–7.43 (m, 5H), 7.40–7.00 (m, 9H), 5.02–4.95 (m, 0.5H),4.80–4.72 (m, 0.5H), 4.59–4.46 (m, 1H), 4.30–4.19 (m, 1.5H), 4.01–3.95(m, 0.5H), 3.77–3.60 (m, 2.5H), 3.40–2.58 (m, 9H), 1.82 (dd, 0.5H,J=8,17 Hz).

Example 7

(2R)-4-[(2R)-2-Benzylpiperazin-1-yl]-1-(2-fluorophenyl)-4-oxobutan-2-amine,bis trifluoroacetate salt. To a solution of 502 mg (0.92 mmol) of thetert-butyl carbamate of(2R)-4-[(2R)-2,4-dibenzylpiperazin-1-yl]-1-(2-fluorophenyl)-4-oxobutan-2-aminein 20 mL of methanol, palladium hydroxide on activated carbon (˜300 mg)was added, and the mixture was stirred under a balloon of hydrogen for24 h. The reaction was diluted with methanol, filtered through a pad ofCelite, and concentrated in vacuo to afford the desired product. Aportion of the material was purified by preparative TLC (silica gel, 5%methanol in methylene chloride), and then deprotected as described inExample 1, Step A, to give the title compound which was isolated as itsbistrifluoroacetate salt and not purified further. 1H NMR (400 MHz,CD₃OD) δ 7.40–7.00 (m, 9H), 5.15–5.05 (m, 0.5H), 4.77–4.68 (m, 0.5H),4.32–4.25 (m, 0.5H), 3.95–3.85 (m, 0.5H), 3.75–3.56 (m, 1.5H), 3.43–3.20(m, 3H), 3.19–2.82 (m, 5H), 2.80–2.65 (m, 1.5H), 2.58–2.50 (m, 0.5H),1.68 (dd, 0.5H, J=8.17 Hz).

Example 8

2-{(3R)-4-[(3R)-3-Amino-4-(2-fluorophenyl)butanoyl]-3-benzylpiperazin-1-yl}acetamide,bis trifluoroacetate salt. To a solution of 50 mg (0.11 mmol) of thetert-butyl carbamate of(2R)-4-[(2R)-2-benzylpiperazin-1-yl]-1-(2-fluorophenyl)-4-oxobutan-2-aminein 1 mL of N,N-dimethylformamide was added 31 mg (0.33 mmol) of2-chloroacetamide and 0.1 mL (0.57 mmol) of diisopropylethylamine. Thereaction mixture was stirred at ambient temperature for 16 h, dilutedwith ethyl acetate, washed with water and brine, dried over magnesiumsulfate, and concentrated in vacuo. Purification by preparative TLC(silica gel, 5% methanol in methylene chloride) gave 24 mg of coupledproduct, which was deprotected as described in Example 1, Step A, togive 28 mg of the title compound which was isolated as itsbistrifluoroacetate salt and not purified further. ¹H NMR (400 MHz,CD₃OD) δ 7.40–7.10 (m, 9H), 5.02–4.93 (m, 0.5H), 4.75–4.66 (m, 0.5H),4.23–4.17 (m, 0.5H), 3.97–3.80 (m, 1.5H), 3.76–3.60 (m, 2.5H), 3.55–3.30(m, 2.5H), 3.19–2.65 (m, 7H), 2.60–2.53(m, 0.5H), 1.82 (dd, 0.5H, J=8.17Hz).

Example 9

(2R)-4-[(2R)-2-Benzyl-4-methylpiperazin-1-yl]-1-(2-fluorophenyI)-4-oxobutan-2-amine,bistrifluoroacetate salt. To a solution of 88 mg (0.20 mmol) of thetert-butyl carbamate of(2R)-4-[(2R)-2-benzylpiperazin-1-yl]-1-(2-fluorophenyl)-4-oxobutan-2-aminein 2.5 mL of 1,2-dichloroethane was added 100 mg (0.47 mmol) of sodiumtriacetoxyborohydride, 100 mg of paraformaldehyde, and 4A molecularsieves. The reaction mixture was stirred at ambient temperature for 16h, diluted with ethyl acetate, washed sequentially with saturated sodiumbicarbonate solution, water and brine, dried over magnesium sulfate, andconcentrated in vacuo. Purification by preparative TLC-(silica gel, 5%methanol in methylene chloride) gave 77 mg of coupled product, which wasdeprotected as described in Example 1, Step A above, to give 80 mg ofthe title compound which was isolated as its bistrifluoroacetate saltand not purified further. ¹H NMR (400 MHz, CD₃OD) δ 7.40–7.08 (m, 9H),5.20–4.08 (m, 0.5H), 4.80–4.75 (m, 0.5H), 4.38–4.30 (m, 0.5H), 3.98–3.91(m, 0.5H), 3.72–3.40 (m, 3.5H), 3.40–2.80 (m, 9H), 2.79–2.63 (m, 1.5H),2.58–2.47(m, 0.5H), 1.65 (dd, 0.5H, J=8.17 Hz).

Following the procedures outlined for Examples 1–9, the compounds listedin Tables 1–3 were prepared as their bistrifluoroacetate salts (unlessotherwise noted).

TABLE 1

Selected ¹H NMR data Example Ar Q R⁷ of trifluoroacetate salts. 103,4-diF—Ph Bn

7.71(s, 1H), 7.40–6.93(m, 11H), 2.97(s, 3H) 11 3,4-diF— H H 7.30–7.21(m,2H), 7.12– Ph 7 08(m, 1H) 12 3,4-diF—Ph H

7.68(t, 1H, J=1.8Hz),7.36–7.22(m, 5H),7.12–7.08(m, 1H), 6.98(d, 1H,J=7.8Hz)4.14(s, 2H), 2.97(s, 3H) 13 3,4-diF—Ph Bn

7.73(s, 1H), 7.41–6.94(m, 11H), 4.17–4.05(m,2H) 14 3,4-diF—Ph Bn

7.62–7.58(m 1H), 7.39–6.91(m, 12H) 15 3,4-diF—Ph Ph

7.61(s, 1H), 7.55–7.35(m, 5H), 7.34–7.05(m,5H), 6.99(d, 1H, J=8Hz),2.97(s, 3H) 16 3,4-diF—Ph CH₂(3-indole)

7.83–7.73(m, 2H),7.60–7.53(m, 1H),7.41–6.73(m, 9H),4.17–3.99(m, 2H) 173,4-diF— 4-BrBn Bn 7.58–7.45(m, 5H), Ph 7.41–7.10(m, 4H), 7.09–6.95(m,3H) 18 2-F—Ph H H 7.39–7.30(m, 2H), 7.21–7.10(m, 2H) 19 2-F—Ph H

7.67(t, 1H, J=2Hz),7.39–7.26(m, 4H),7.22–7.13(m, 2H), 6.97(d, 1H,J=7.8Hz), 4.09(s, 2H), 2.97(s, 3H) 20 2-F—Ph H

8.69(d, 1H, =4.5Hz),7.98(td, 1H, J=7.7, 1.6Hz), 7.58–7.50(m, 2H),7.38–7.31(m,2H), 7.21–7.12(m, 2H),4.47(s, 2H) 21 2-F—Ph H

8.78(d, 1H, J=1.8Hz),8.74(dd, 1H, J=1.3, 5.3Hz), 8.27(d, 1H,J=8Hz),7.78(dd, 1H,J=5.3, 8Hz), 7.39–7.31(m, 2H), 7.21–7.12(m,2H), 4.28(s, 2H)22 2-F—Ph H

7.70(d, 1H, J=7.9Hz),7.54(s, 1H), 7.45(d,1H, J=8.0Hz), 7.34–6.99(m, 6H),4.58(s,2H) 23 2-F—Ph H

2.27(s, 3H), 2.00(s,6H), 1.83–1.70(m, 6H) 24 2-F—Ph H

3.36(s, 1H), 2.43 (s,2H), 2.08–1.89(m, 6H),1.88–1.73(m, 6H) 25 2-F—Ph H

3.99–3.61(m, 6H), 3.57(dd, 1H, J=12.5,8.2Hz), 3.42–3.30(m,2H),3.26–2.98(m, 8H),2.40–2.27(m, 1H) 26 2-F—Ph H

Free base: 6.15(s, 1H),4.49(s, 2H), 3.97(s,6H) 27 2-F—Ph H

7.53–4.47(m, 1H), 7.42(dd, 1H, 1.6, 7.7Hz),7.20–7.11(m, 3H), 7.06(t, 1H,J=7.5Hz), 4.38(s, 2H), 3.92(s, 3H) 28 2-F—Ph H

8.02(d, 1H, J=8.2Hz),7.91(d, 1H, J=8.2Hz), 7.56–7.52(m,1H), 7.46–7.42(m,1H) 29 2-F—Ph H

8.36(d, 1H, J=8.4Hz),8.06–7.98(m, 2H),7.85–7.81(m, 2H), 7.59(d, 1H,J=6.8Hz) 30 2-F—Ph H

8.73(s, 1H), 8.28(d,1H, J=8.4Hz), 8.05(t,1H, J=8.0Hz), 7.82(d,1H, J =8.4Hz),7.79 –7.75(m, 1H) 31 2-F—Ph H

6.78(t, 1H, J=8.0Hz),6.63(dd, 1H, J=1.3, 8.2Hz), 6.59(dd,1H, J=1.3,8.0Hz),4.32–4.20(m, 4H) 32 2-F—Ph H

7.38–7.12(m, 8H), 4.13(quin, 1H, J=7.8Hz),3.44–3.20(m, 12H) 33 2-F—Ph Bn

7.75(s, 1H), 7.41–7.08(m, 11H), 7.01(d, 1H,J=7.8Hz), 4.16–4.05(m, 2H) 342-F—Ph Bn

7.62–7.55(m, 1H), 7.41–7.00(m, 13H) 35 2-F—Ph Bn Ph 7.41–7.07(m, 11H),6.99–6.82(m, 3H) 36 2-F—Ph Bn 2-MeOPh 7.42–6.86(m, 13H), 3.88(s, 1.2H),3.87(s, 0.75, 3.86s, 1.05H) 37 2-F—Ph CH₂CO₂Me

7.65(s, 1H), 7.39–7.25(m, 4H0, 7.21–7.11(m,2H), 6.97(d, 1H, J=8Hz),2.96(s, 3H) 38 2-F—Ph CH₂CO₂H

7.65(s, 1H), 7.38–7.25(m, 4H), 7.21–7.11(m,2H), 6.97(d, 1H, J=8Hz),2.97(s, 3H) 39 2-F—Ph Ph

7.63(s, 1H), 7.55–7.10(m, 11H), 6.99(d, 1H,J=8Hz), 2.97(s, 3H) 40 2-F—PhCH₂(3-indole)

7.83–7.70(m, 2H),7.60–7.45(m, 1H),7.40–7.25(m, 4H),7.23–7.05(m,4H),7.01–6.95(m, 2H),4.17–3.99(m, 2H) 41 2-F—Ph 4-BrBn Bn 7.55–7.43(m,5H), 7.1– 7.10(m, 6H), 7.05(d, 0.5H, J=8Hz), 6.97(d, 1H, J=8Hz), 6.92(d,0.5H, J=8Hz), 42 Ph Bn

7.72(s, 1H), 7.41–7.10(m, 12H), 6.99(d, 1H,J=8Hz), 2.98(s, 3H) 43 4-ClPhBn

7.70(s, 1H), 7.41–7.08(m, 11H), 6.99(d, 1H,J=8Hz), 2.98(s, 3H)

TABLE 2

Selected ¹H NMR data of Example Ar Q R⁷ trifluoroacetate salts 443,4-diF—Ph Bn Bn 7.58–7.43(m, 5H), 7.31– 6.98(m, 8H) 45 3,4-diF—Ph Bn H7.38–7.07(m, 7H), 7.08– 6.98(m, 111) 46 3,4-diF—Ph 4-F—PhCH₂ Bn7.56–7.45(m, 5H), 7.28– 6.81(m, 7H) 47 3,4-diF—Ph 4-F—PhCH₂ H7.29–7.21(m, 3H), 7.21– 7.17(m, 1H), 7.12–6.93(m, 3H) 48 3,4-diF—Ph3,4-F— Bn 7.52–7.48(m, 5H), 7.30– PhCH₂ 6.93(m, 5H), 6.92–6.82(m, 1H) 493,4-diF—Ph 3,4-F— H 7.30–7.15(m, 3H), 7.14– PhCH₂ 7.00(m, 3H) 503,4-diF—Ph 4-F—Ph Bn 7.57—7.47(m, 5H), 7.30– 7.03(m, 7H) 51 3,4-diF—Ph4-F—Ph H 7.46–7.03(m, 7H) 52 2-F—Ph ^(i)Pr Bn 1.80–1.65(m, 1H), 1.52–1.35(m, 2H), 0.92–0.83(m, 6H) 53 2-F—Ph ^(i)Pr H 1.80–1.62(m, 1H), 1.59–1.40(m, 2H), 0.96–0.86(m, 6H) 54 2-F—Ph Me Bn 1.39–1.20(m, 3H) 55 2-F—PhMe H 1.40–1.23(m, 3H) 56 2-F—Ph 4-F—PhCH₂ Bn 7.56–7.43(m, 5H), 7.39–7.03(m, 6H), 7.00–6.79(m, 2H) 57 2-F—Ph 4-F—PhCH₂ H 7.39–7.35(m, 1H),7.30– 7.03(m, 6H), 6.95(t, 1H, J= 10Hz) 58 2-F—Ph 3,4-F— Bn 7.55—7.43(m,5H), 7.39— PhCH₂ 7.22(m, 2H), 7.21–6.93(m, 4H), 6.90–6.81(m, 1H) 592-F—Ph 3,4-F— H 7.39–6.98(m, 7H) PhCH₂ 60 2-F—Ph 4-F—Ph Bn 7.57–7.47(m,5H), 7.42– 7.08(m, 8H) 61 2-F—Ph 4-F—Ph H 7.50–7.00(m, 8H) 623-thiophene Bn H 7.46(dd, 1H, J=3,5Hz), 7.38-7.10(m, 6H), 6.97(d, 1H,4.7Hz)

TABLE 3

Selected ¹H NMR data of Example Ar Q trifluoroacetate salts 63 3,4-diF—Bn 7.31–6.92(m, 8H), 1.91– Ph 1.60(m, 4H), 1.58–1.30(m, 2H) 64 2-F—Ph Bn7.40–7.01(m, 9H) 65 2-F—Ph H 7.39–7.31(m, 2H), 7.20– 7.12(m, 2H),1.70–1.61(m, 2H), 1.58–1.50(m, 4H) 66 2-F—Ph Me 1.22–1.11(m, 3H)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: X is NR⁷; Ar isselected from the group consisting of: (1) phenyl and (2) naphthyl,wherein Ar is optionally substituted with 1–5 groups R¹; R¹is selectedfrom the group consisting of: (1) halogen, (2) C₁₋₆alkyl, which islinear or branched and is optionally substituted with 1–5 halogens, (3)OC₁₋₆alkyl, which is linear or branched and is optionally substitutedwith 1–5 halogens, and (4) CN; Each R² is independently selected fromthe group consisting of H, OH, halogen and C₁₋₆alkyl, wherein C₁₋₆alkylis linear or branched and is optionally substituted with 1–5 halogens,wherein the two groups R² can optionally be joined to form aC₃₋₆cycloalkyl, which is optionally substituted with 1–3 halogens; EachR³ is independently selected from the group consisting of H, halogen andC₁₋₆alkyl, wherein C₁₋₆alkyl is linear or branched and is optionallysubstituted with 1–5 halogens, wherein the two groups R³ can optionallybe joined to form a C₃₋₆cycloalkyl, which is optionally substituted with1–3 halogens; Q is selected from the group consisting of: (1) H, (2)C₁₋₁₀alkyl, which is linear or branched and is optionally substitutedwith 1–6 substituents independently selected from 0–5 halogens and 0–1substituent selected from (a) phenyl, (b) naphthyl, (c) a 5 or6-membered heterocycle which may be saturated or unsaturated comprising1–4 heteroatoms independently selected from N, S and O, (d) an 8–10membered bicyclic ring system which may be saturated or unsaturatedwhich comprises (a) two fused heterocyclic rings, each heterocyclic ringhaving 1–4 heteroatoms independently selected from N, S and O, or (b) aphenyl ring fused to a 5- or 6-membered heterocycle having 1–3heteroatoms selected from N, S and O, (e) CO₂H, (f) CO₂C₁₋₆alkyl, and(g) CONR⁴R⁴ wherein said phenyl and naphthyl are optionally substitutedwith 1–5 substituents independently selected from C₁₋₆alkyl, OC₁₋₆alkyl,hydroxy and halogen, said C₁₋₆alkyl and OC₁₋₆alkyl being linear orbranched and optionally substituted with 1–5 halogens, and wherein saidCO₂C₁₋₆alkyl is linear or branched, and wherein said 5 or 6-memberedheterocycle and said 8–10 membered bicyclic ring system are optionallysubstituted with 1–5 substituents independently selected from C₁₋₆alkyl,OC₁₋₆alkyl, oxo, hydroxy and halogen, said C₁₋₆alkyl and OC₁₋₆alkylbeing linear or branched and optionally substituted with 1–5 halogens,and wherein said CO₂C₁₋₆alkyl is linear or branched; (3) CN; (4) Phenyl,which is optionally substituted with 1–5 substituents independentlyselected from C₁₋₆alkyl, OC₁₋₆alkyl, hydroxy and halogen, said C₁₋₆alkyland OC₁₋₆alkyl being linear or branched and optionally substituted with1–5 halogens; (5) Naphthyl, which is optionally substituted with 1–5substituents independently selected from C₁₋₆alkyl, OC₁₋₆alkyl, hydroxyand halogen, said C₁₋₆alkyl and OC₁₋₆alkyl being linear or branched andoptionally substituted with 1–5 halogens, (6) a 5 or 6-memberedheterocycle which may be saturated or unsaturated comprising 1–4heteroatoms independently selected from N, S and O, said heterocyclebeing optionally substituted with 1–5 substituents independentlyselected from oxo, hydroxy, C₁₋₆alkyl, OC₁₋₆alkyl and halogen, saidC₁₋₆alkyl and OC₁₋₆alkyl being linear or branched and optionallysubstituted with 1–5 halogens, and (7) an 8–10 membered bicyclic ringsystem which may be saturated or unsaturated which comprises (a) twofused heterocyclic rings, each heterocyclic ring having 1–4 heteroatomsindependently selected from N, S and O, or (b) a phenyl ring fused to a5-or 6-membered heterocycle having 1–3 heteroatoms selected from N, Sand O, wherein said bicyclic ring system is optionally substituted with1–5 substituents independently selected from oxo, hydroxy, C₁₋₆alky,OC₁₋₆alkyl and halogen, said C₁₋₆alkyl and OC₁₋₆alkyl being linear orbranched and optionally substituted with 1–5 halogens; R⁴ is selectedfrom (1) H, and (2) R⁵; R⁵ is selected from the group consisting ofphenyl, C₃₋₆cycloalkyl and C₁₋₆alkyl, wherein C₁₋₆alkyl is linear orbranched and is optionally substituted with 1–6 substituentsindependently selected from 0–5 halogens and 0–1 phenyl, wherein saidoptional phenyl substituent and said R⁵ when R5 is phenyl orC₃₋₆cycloalkyl are optionally substituted with 1–5 substituentsindependently selected from halogen, OH, C₁₋₆alkyl, and OC₁₋₆alkyl, saidC₁₋₆alkyl and OC₁₋₆alkyl being linear or branched and optionallysubstituted with 1–5 halogens; and R⁷ is selected from the groupconsisting of (1) H, (2) C₁₋ ₆alkyl which is linear or branched and isoptionally substituted with 1–6 substituents independently selected from0–5 halogens and 0–1 substituents selected from (a) phenyl, (b)naphthyl, (c) a 5 or 6-membered heterocyclic ring which may be saturatedor unsaturated comprising 1–4 heteroatoms independently selected from N,S and O, (d) an 8–10 membered bicyclic ring system which may besaturated or unsaturated which comprises (a) two fused heterocyclicrings, each heterocyclic ring having 1–4 heteroatoms independentlyselected from N, S and O, or (b) a phenyl ring fused to a 5- or6-membered heterocycle having 1–3 heteroatoms selected from N, S and O,(e) C(═O)NR⁴R⁴, wherein said phenyl, naphthyl, and R⁴ when R⁴ is phenylor C₃₋₆cycloalkyl are optionally substituted with 1–5 substituentsindependently selected from halogen, OH, nitro, C₁₋₆alkyl, OC₁₋₆alkyl,and NHSO₂C₁₋₆alkyl, said C₁₋₆alkyl, OC₁₋₆alkyl and NHSO₂C₁₋₆alkyl beinglinear or branched and optionally substituted with 1–5 halogens, andwherein said 5-6-membered heterocycle and 8–10 membered bicyclic ringsystem are optionally substituted with 1–5 substituents independentlyselected from halogen, oxo, OH, C₁₋₆alkyl, OC₁₋₆alkyl, andNHSO₂C₁₋₆alkyl, said C₁₋₆alkyl, OC₁₋₆alkyl and NHSO₂C₁₋₆alkyl beinglinear or branched and optionally substituted with 1–5 halogens, (3)Phenyl, which is optionally substituted with 1–5 substituentsindependently selected from halogen, OH, C₁₋₆alkyl and OC₁₋₆alkyl, saidC₁₋₆alkyl and OC₁₋₆alkyl being linear or branched and optionallysubstituted with 1–5 halogens, (4) a 5 or 6-membered heterocycle whichmay be saturated or unsaturated comprising 1–4 heteroatoms independentlyselected from N, S and O, wherein said heterocycle is optionallysubstituted with 1–5 substituents independently selected from halogen,oxo, OH, C₁₋₆alkyl and OC₁₋₆alkyl, said C₁₋₆alkyl and OC₁₋₆alkyl beinglinear or branched and optionally substituted with 1–5 halogens, (5) an8–10 membered bicyclic ring system which may be saturated or unsaturatedwhich comprises (a) two fused heterocyclic rings, each heterocyclic ringhaving 1–4 heteroatoms selected from N, S and O, or (b) a 5- or6-membered heterocycle having 1–3 heteroatoms selected from N, S and Ofused to a phenyl ring, wherein said bicyclic ring system is optionallysubstituted with 1–5 substituents independently selected from halogen,oxo, OH, C₁₋₆alkyl and OC₁₋₆alkyl, said C₁₋₆alkyl and OC₁₋₆alkyl beinglinear or branched and optionally substituted with 1–5 halogens, (6)adamantyl, which is optionally substituted with 1–5 substituentsindependently selected from halogen, OH, C₁₋₆alkyl and OC₁₋₆alkyl, saidC₁₋₆alkYl and OC₁₋₆alkyl being linear or branched and optionallysubstituted with 1–5 halogens; (7) naphthyl, which is optionallysubstituted with 1–5 substituents independently selected from halogen,OH, C₁₋₆alkyl and OC₁₋₆alkyl, said C₁₋₆alkyl and OC₁₋₆alkyl being linearor branched and optionally substituted with 1–5 halogens; and (8) a 5–6membered cycloalkyl fused to a phenyl ring, wherein said cycloalkyl maybe saturated or unsaturated, wherein said cycloalkyl and fused phenylring are optionally substituted with 1–5 substituents independentlyselected from halogen, OH, C₁₋₆alkyl and OC₁₋₆alkyl, said C₁₋₆alkyl andOC₁₋₆alkyl being linear or branched and optionally substituted with 1–5halogens; with the proviso that X is not N−Me.
 2. A compound of formulaI as recited in claim 1, wherein R₂ and R₃ are H.
 3. A compound offormula I as recited in claim 1, wherein Ar is phenyl, optionallysubstituted as in claim
 1. 4. A compound of formula I as recited inclaim 1, wherein Q is selected from the group consisting of phenyl andCH₂phenyl, optionally substituted as in claim
 1. 5. A compound offormula I as recited in claim 1, wherein X is NR⁷, and R⁷ is CH₂, whichis substituted with 1 substituent selected from (a) phenyl; (b)naphthyl; (c) a 5 or 6-membered heterocyclic ring which may be saturatedor unsaturated comprising 1–4 heteroatoms independently selected from N,S and O; (d) an 8–10 membered bicyclic ring system which may besaturated or unsaturated which comprises (a) two fused heterocyclicrings, each heterocyclic ring having 1–4 heteroatoms independentlyselected from N, S and O, or (b) a phenyl ring fused to a 5-or6-membered heterocycle having 1–3 heteroatoms selected from N, S and O,and (e) C(═O)NR⁴R⁴, wherein R⁴ is as previously defined, and saidphenyl, naphthyl, and R⁴ when R⁴ is phenyl or C₃₋₆cycloalkyl areoptionally substituted with 1–5 substituents independently selected fromhalogen, OH, C₁₋₆alkyl, OC₁₋₆alkyl, and NHSO₂C₁₋₆alkyl, said C₁₋₆alkyl,OC₁₋₆alkyl and NHSO₂C₁₋₆alkyl being linear or branched and optionallysubstituted with 1–5 halogens, and wherein said 5-6-membered heterocycleand 8–10 membered bicyclic ring system are optionally substituted with1–5 substituents independently selected from halogen, oxo, OH,C₁₋₆alkyl, OC₁₋₆alkyl, and NHSO₂C₁₋₆alkyl, said C₁₋₆alkyl, OC₁₋₆alkyland NHSO2C₁₋₆alkyl being linear or branched and optionally substitutedwith 1–5 halogens.
 6. A compound of Formula I as recited in claim 1,wherein said 8–10 membered bicyclic ring system is selected from thegroup consisting of indole, indoline, benzofuran, benzothiophene,benzoxazole, benzisoxazole, benzothiazole, benzisothiazole,benzimidazole, benzimidazoline, quinoline, quinazoline,dihydroquinazoline, dihydroquinoline, isoquinoline,tetrahydroisoquinoline, and dihydroisoquinoline.
 7. A compound ofFormula I as recited in claim 1, wherein said 5-or 6-memberedheterocycle is selected from the group consisting of furan, thiophene,pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline,oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline,isothiazole, isothiazoline, thiadiazole, thiadiazoline, tetrahydrofuran,tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine,oxazolidine, isoxazolidine, thiazolidine, isothiazolidine,thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran,imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine,piperidine, morpholine, tetrazole, triazole, triazolidine, andtetrazolidine.
 8. A compound of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,R⁵, R⁷, Q, X and Ar are as previously defined in claim 1; with theproviso that X is not N-Me.
 9. A compound of Formula Ib:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,R⁵, R⁷, Q, X and Ar are as previously defined in claim 1; with theproviso that X is not N-Me.
 10. A pharmaceutical composition comprisinga compound of claim 1 and a pharmaceutically acceptable carrier.
 11. Amethod for treating non-insulin dependent (Type 2) diabetes mellitus ina mammalian patient in need of such treatment which comprisesadministering to said patient a therapeutically effective amount of acompound of claim 1.